The New Mechanisms Of Selenoproteins R In Intervention Of Alzheimer’s Disease

Alzheimer’s disease(AD) is a major cause of dementia in the elderly which has the highest incidence of neurodegenerative diseases. It’s clinical symptons are memory loss, cognitive deficiency and behavioral disorders. The pathological features of AD are senile plaques(SP), resulted from amyloid-β(Aβ) deposition outside neurons, and neurofibrillary tangles(NFT), caused by tau hyperphosphorylation. In addition, oxidative stress, neuronal loss and metal ion dyshomeostasis are closely related to AD. In the AD brain, A large number of transition metal ions including copper, iron and zinc ions were found in the brain of AD patients, which promoted Aβ aggregation and reactive oxygen species(ROS) generation, leading to neuronal damage and functional loss. Thus, Aβ aggregation and cytotoxicity induced by transition metal ions in neuronal cells have been considered as two major causes of AD. Meanwhile, cofilinactin rods were found in the frontal cortex and hippocampus of AD brain, but not in normal human brain. The formation of cofilin-actin rods is related to neurodegenerative diseases. This shows that AD may be related to structural change of actin caused by cofilin dysfunction.Selenoprotein R(SelR) is one of the key member of selenoproteins family, which contains the 21 st essential amino acids, selenocysteine(Sec). SelR belongs to the family of methionine sulfoxide reductase, which can stereospecific catalyzed the reduction of R-type methionine sulfoxide. As a special protein, SelR has active redox property and it is involved in the repairment of oxidatively damaged proteins.Our previous study found that SelR can affect Aβ aggregation and tau hyperphosphorylation. The present paper aimed at investigating the binding property of SelR with copper ions and its ability to modulate the aggregation and neurotoxicity of Aβ42. Meanwhile, the relationship between SelR and RhoA/ROCK pathway was also studied. The results showed that SelR could compete for Cu+ with bicinchoninic acid(BCA), a specific Cu+ chelator, suggesting the high binding affinity between SelR and Cu+. Using thioflavine T fluorescence assay, it was observed that Cu2+/Cu+ binding to Aβ42 almost completely suppressed Aβ42 fibrillization, leading to the nonfibrillar aggregation of Aβ42, which could be significantly restored by SelR. Using CCK-8 assay, SelR was found to inhibit Cu+/Cu2+-Aβ42 induced neurotoxicity. The expression levels of hippocampal protein in triple transgenic AD mice were also detected and compared with wild-type mice. Sel R expression was found significantly decreased in AD mice, while the expression levels of RhoA, ROCK1 and p-cofilin are increased significantly. When SelR was knocked down in N2 a cells, the expression levels of RhoA, ROCK1 and p-cofilin were also increased significantly compared with the control group, indicating that SelR can affect the RhoA/ROCK pathway to influence the development of neurons, thus has an impact on the pathological process of AD.In summary, this study demonstrated SelR could inhibit aggregation and cytotoxicity of Aβ42 induced by copper ions through competitively binding with Cu2+/Cu+. Meanwhile, SelR could also modulate the RhoA/ROCK pathway, thus regulate actin assembly and inhibit axonal damage. This study reveals two new mechanisms of SelR in intervening AD progression through binding with metal ions and regulating neural development.